19-nor-delta4-9beta, 10alpha-17, 21-diol-pregnane derivatives



United States Patent 3,230,217 19-NQR-A -913,1Dot-17,21-D1OL-PREGNANE DERIVATIVES Albeit Bowers, John Edwards, and Pierre Crabbe, Mexico City, Mexico, assignors to Syntax Corporation, Panama,

Panama, a corporation of Panama No Drawing. Filed Aug. 26, 1963, Ser. No. 304,681 20 Claims. ((11. 260-23955) The present invention relates to certain new cyclopentanophenanthrene derivatives.

More particularly, the present invention relates to the novel 19-nor-corticoids With abnormal configuration at the centers of asymmetry of the steroid skeleton, particularly at carbon atoms 9 and 10, which are further substituted at C-6 and/ or C16.

The transformation of the normal steroid configuration of 19-nor-steroids into the 9B,10u-configuration has been found to have a remarkable etfect on the physiological properties of the compounds in comparison with those of the normal 9cc,10B-SI1ES.

The compounds of the present invention are valuable cortical hormones with high anti-infiammatory, low catabolic, glycogenic and thymolytic activities. In addition, they are anti-androgenic, anti-gonadotrophic and anti-estrogenic hormones. Furthermore, they have high topical activity in skin disorders such as psoriasis, allergic dermatitis and the like.

The novel compounds of the present invention are represented by the following formulas CHQOR i=0 n l OIQIV A O:

CHzOR :0 xAijifa a (ft 0: 0

CHzOR wherein R and R have the meaning hereinbefore indicated; X represents hydrogen or methyl; X represents chlorine or fluorine; X represents hydrogen, methyl, chlorine or fluorine; and Y represents hydrogen, ,B-hydroxy and keto.

The acyl groups above referred to are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetic, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and ,B-chloropropionate.

The compounds represented by A and B are obtained by the process illustrated by the following equation:

In the above formulas R, R R R X and Y have the same meaning as heretofore set forth.

In practicing the process just outlined, the starting materials A 19 nor-93,10a-pregnene-17a,21-diol-3,20- dione, A 19-nor-913,10a-pregnene-11B,17a,21-triol-3,20- dione, A 19 nor-9d,10a-pregnene-17u,21-diol-3,11,20- trione and the 6a-methyl derivatives thereof (I), described in our copending patent application Serial No. 210,211, filed July 16, 1962, are subjected to microbiolog ical oxidation with the microorganism Streptomyces roseochromogenus, to thus form the corresponding 16ozhydroxylated derivatives (II; R and R =H). Conventional esterification of these compounds with hydrocarbon carboxylic acid anhydrides of less than 12 carbon atoms in pyridine solution produce the 16,21-diesters (H; R and R =acyl) By reaction of the free compounds with a ketone or aldehyde such as acetone, butanone, acetophenone, formaldehyde, acetaldehyde and the like, in the presence of catalytic amounts of perchloric acid there are produced the corresponding cyclic ketals or cyclic acetals (III; R=H) which upon conventional esterification give the respective 21-esters (III; R=acyl).

nene derivatives of formula C are obtained by the following sequence of reactions:

a HOQ In the above formulas, R, R and X have the same meaning 'as heretofore indicated; and Y represents hydrogen or a ketogroup.

In practicing the process outlined above the starting materials, i.e. the 17,20;20,2l-bismethylenedioxy derivatives of A -19-nor-9fi, a-pregnene-17u,21-diol-3,20- dione, A 19 nor 96, 10a-pregnene-17og21-diol-3,11,20- trione, 160: or 16/3-methyl-A -19-nor-9fl, wot-pregnene- 17a,21-diol-3,20-dione, 16cc or 16fl-methyl-M-19-nor-9fl, 10a pregnene 17cc, 2l-diol-3,11,2Otrione,A -19-nor-9,8, 10a-pregnene-16a,17u,21-triol-3,20-dione, and A -19-nor- 9,8,10ot pregnene 16oc,17a,21 triol 3,11,20-trione (IV) are treated with ethyl orthoformate in dioxane solution and in the presence of p-toluenesulfonic acid, to produce the corresponding 3 enol ethers (V). By reaction of these compounds with approximately 1 molar equivalent of N-chlorosuccinimide in acetone solution and in the presence of sodium acetate, there are obtained the 6,8- chloro intermediates, which upon acid treatment, preferably by reaction with anhydrous hydrogen chloride at low temperature are isomerized to the 6a-chloro compounds (VI: X =chlorine).

When the 3 enol ethers (V) are reacted with perchloryl fluoride in dimethyl formamide solution, at low temperature, preferably around 0 0., there are produced the 6,8-fluoro-A -3-keto compounds which upon isomerization with dry hydrogen chloride in acetic acid afford the 6DL-flUOrO derivatives (VI; X =F) By hydrolysis of the bismethylenedioxy group in a conventional manner, preferably by reflux with 60% formic acid, there are produced the 6a-chloro and 60efluoro derivatives of A -19-nor-9fi,10u-pregnene-17a,21- diol 3,20-dione, A -19-nor-9fi,wot-pregnene-17u,21-diol 3,11,20-trione and those of the corresponding 16-substituted compounds (VII; R=H).

By reduction of the 6m halo 17,20;20,2l-bismethylenedioxy-ll-keto compounds (VI; Y =keto) with lithium aluminum hydride in tetrahydrofuran, at reflux temperature, there are produced the 3B,1l-dihydroxy compounds (VIII), which upon selective oxidation with manganese dioxide in chloroform or 2,3-dichloro-5,6-dicyano-1,4- benzoquinone in dioxane, at room temperature, afford the 11-hydroxyA -3-keto compounds (IX). The bismethylenedioxy group is then hydrolyzed with 60% formic acid, to produce the 6oc-ChlOr0 and 6u-fluoro derivatives of A 19 nor 95,10a-pregnene-11B,17a,21-triol-3,20- dione, 16oz methyl A 19-nor-9,B,10a-pregnene-11B, 17a,21 triol 3,20-dione, 16,8-methyl-A -19-nor-9fl,10apregnene 11B,17a,21-triol-3,20-dione and A -19-nor-9fi, 10a pregnene 11fi,16x,17oz,2l tetrol 3,20 dione (X; R=H).

By reaction of the Soc-ChlOIO and Got-fluoro compounds further substituted at C-16oc by a hydroxyl group (VII and X; R=H, R =OH) with a ketone or aldehyde of the type previously mentioned there are produced the corresponding 16oc,17ocCyCliC ketals and acetals.

Conventional esterification of compounds VII and X (R=H) with carboxylic acid anhydrides of less than 12 carbon atoms in pyridine solution afford the respective esters.

By treatment of the 21-esters of A -19-nor-9B,10apregnene 1711,21 diol 3,20-dione, A 19I1OI-9B,100cpregnene 11fi,l7a,21 triol 3,20 dione, A -19-nor- 9fi,10oc pregnene 17oc,21 diol-3,11,20-trione, the 60cchloro, 6oc-fluOIO, Goa-methyl and 16-substituted derivatives thereof with a quinone having an oxidation-reduction potential of less than 0.5, such as benzoquinone, chloranil (tetrachlorobenzoquinone), 2,6-dichlorobenzoquinone and the like, at reflux temperature in t-butyl alcohol, t-amyl alcohol, xylene, toluene, etc., there are produced the corresponding 6-dehydro compounds, which can optionally be saponified by conventional methods, for example, by reaction with dilute potassium hydroxide solution in methanol, at low temperature and under nitrogen atmosphere.

Alternatively, the introduction of a double bond at (3-6 can be effected in the bismethylenedioxy compounds (VI and VII) which upon hydrolysis with 60% formic acid give the 6 halo A -19-nor95,IOa-pregnadiene compounds.

Among the compounds thus obtained, there are A- 19 9fi,10o: pregnadience 17a,21-diol-3,20-dione, A 19 nor 9fi,10a-pregnadiene-11B,l7a,21-triol-3,20-dione, A 19 nor 96,1011 pregnadiene-1704,21-di0l-3,11,20- trione, 16B methyl A 19-nor-9B,met-pregnadiene- 1705,21 diol 3,20 dione, 16oz methyl A 19- nor 9,8,100: pregnadiene 1lfi,17ot,21 triol 3,20- dione, :,170: isopropylidenedioxy A -19-nor-9p, 10a pregnadiene 115,21 diol-3,20dione, 6-chloro- A 19 nor 9B,10a-pregnadiene-17a,21-diol-3,20- dione, 6 fluoro A -19-nor-9fl,10u-pregnadiene-11B, :,21 triol 3,20 dione, 6-fluoro-16u-methyl-A -19- nor 95,100: pregnadiene 115,17a,21-triol-3,20-dione, 6 methyl A 19 nor 9fi,10 x pregnadiene-17a,21- diol 3,11,20 trione, 6,160: dimethyl A -19-nor- 9 6,100: pregnadiene 11B,17ix,21-triol-3,20-dione, and other similar compounds.

The following examples serve to illustrate but are not intended to limit the present invention:

PREPARATION 1 A solution of 1 g. of the 21-acetate of 16e-methyl-A -19- nor-96,10a-pregnene 115,17a,21 triol 3,20 dione, described in our copending patent application Serial No. 210,211, filed July 16, 1962, in 20 cc. of acetone was cooled to C. and treated under an atmosphere of nitrogen and with stirring, with an 8N solution of chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for minutes further at 0-5 C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave the ZI-acetate of 160t-Hl6thy1- A -l9-nor-9fl,l0ot-pregnene-17u,21-diol-3,11,20-trione.

PREPARATION 2 A cold solution of 2 g. of 16a-methyl-A -l9-nor-918,1O x pregnene-17a,21-diol-3,20-dione 21-acetate in 50 cc. of methanol was treated with 5 cc. of a 4% aqueous solution of potassium hydroxide; the reaction mixture was stirred for 1 hour under an atmosphere of nitrogen at 0 C.; the mixture was neutralized with acetic acid and the methanol distilled under reduced pressure. The residue was triturated with water and the solid collected, washed with water, dried and recrystallized from ethyl acetatemethanol, thus producing 16x-methyl-A -19-nor-913,10apregnene-17u,2l-diol-3,20 dione.

In a similar manner, 6a-methyl-A -19-nor-9B,10a-pregnene-l7a,2 l-diol-3,11,20-trione 21-acetate, 6arnethyl-A'* 19-nor-9,8,10a-pregnene-17e,2ldiol-3,20-dione 21-acetate, 16B-methyl-A -19-nor-9p,IOCt-pregnene l7a,21-diol-3,20- dione 21-acetate, 6u,16adimethyl-A -19-nor-9,8,10a-pregnene-17u,21-diol-3,20-dione ZI-acetate and 16a-methyl-A 19-nor-9B,l0a-pi'egnene-l7a,21-dio1- 3,11,20 trione 21- acetate were converted into the corresponding free compounds.

PREPARATION 3 To a solution of 1 g. of A -19-nor-9,8,IOa-pregnene- 1'7u,21-diol-3,l1,20-trione in 40 cc, of chloroform were added 8 cc. of 37% aqueous formaldehyde and 1 cc. of concentrated hydrochloric acid and the mixture was stirred for 48 hours at room temperature. The two layers were separated; the aqueous layer was washed with chloroform and the combined organic solutions were washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from methanol-ether thus affording l7,20;20,2 l-bismethylenedioxy-A -19-nor-9fi,10a-pregnene-3 ,11-dione.

By the same method, A l9 nor 95,100; pregnene- 17u,21-diol-3,20-dione, 16a-methyl-A -19-nor-95,mot-pregnene-1 711,2 1-diol-3,20-dione, 1SB-methyl-M-19-nor-9B,10apregnenel7u,2-1-dio1-3,20-dione and 16a-methyl-A -l9- nor-9p),10a-pregnene-17a,21-diol-3,1*1,ZO-trione were invetted respectively into 17,20;20,2l-bismethylenedioxy-M- 19-nor-9B,IOa-pregnene-B-one, 16a methyl 17,20;20,21- bismethylenedioxy-n -l9-nor-9,8,IOOL-pregnene-B-one, 16B- methyl-17,20;20,21 bismethylenedioxy-A -19-nor-9,B,10mpregnene-3-one and 16a-methyl-17,20;20,2l-bismethylenedioxy-A -19-nor-9 3,10u-pregnene-3,1 l-dione.

Example I A culture of Streptomyces roseochromogenus ATCC 3347 was prepared in an inclined agar medium containing 1% of glucose and 1% of yeast extract. 1 cc. of a suspension of this culture was then used to innoculate each one of a series of 250 cc. flasks containing 50 cc. of a sterilized aqueous medium of 2% peptone and 5% corn syrup; the mixtures were then incubated in a shaking machine at 28 C. under aereation for a period of 24-48 hours. There was thus obtained a vegetating growing culture of Streptomyces roseochromogenus which was used for the subsequent incubation of the steroid.

10 mg. of A -19-nor-9fi,1Our-pregnene-17a,21-di0l-3,20- dione obtained as described in our copending application Serial No. 210,211 filed July 16, 1962, were added to each 50 cc, of the vegetating culture of Streptomyces roseochromogenus, obtained as described above. The mixture was stirred for 48-72 hours with aereation and then extracted several times with methylene dichloride. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

The residue was purified by chromatography on silica gel thus giving A 19 nor 9fl,10a-pregnene-16a,17 x,21- triol-3,20-dione.

In a similar manner, A -19-nor-9B,l0ot-pregnene-l7ot,2ldiol-3,t1,20-trione was converted into A -19-nor-9B,10upregnene- 16a, 170;,2 1-triol-3 ,11,20-trione.

Example 11 To cc. of acetone containing 1 g. of A -19-nor- 9p,IOa pregnene-16a, l7a,21-triol-3,20-dione were added 30 drops of 70% perchloric acid. After 1 hour at room temperature 30 drops of pyridine were added and the resulting solution was evaporated to dryness under reduced pressure. 30 cc. of water were added to the residue and it was then extracted several times with 80 cc. of ethyl acetate. The combined extracts were washed to neutrality with water, dried over sodium sulfate and evaporated to dryness. The residue upon trituration with methanol gave a crude 16,17-acetonide. Recrystallization from the same solvent furnished 16a,17a-isopropylidenedioxy-M-19-n0r- 9p,10a-pregnene-21-ol-3,20-dione.

Example 111 By following the method of Example I, 1 g. of 60ametl1yl-A -19-nor-9/3,10ot-pregnene-17a,21 diol 3,11,20- trione was converted into 6m-methyl-A -l9-nor-9B,10apregnene-l6a,17a,21-triol-3,11,20-trione.

A solution of 500 mg. of the latter compound in 20 cc. of chloroform was treated with 1 g. of acetaldehyde and a few drops of 3N perchloric acid and stirred at room temperature for 2 hours. After diluting with water the chloroform layer was separated, washed with aqueous saturated sodium bicarbonate solution and then with water, the chloroform was distilled and the residue was purified by chromatography on neutral alumina, thus yielding the 16,17-acetaldehyde acetal of 6ot-methyl-A -19-nor- 95,10a-pregnene-16tx,17a,21-triol-3,11,20-trione.

Example IV A mixture of 1 g. of A -19-nor-9fi,1Oa-pregnene-16a, 17a,21-triol-3,20-dione, 50 cc. of freshly distilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1 hour. The resulting mixture was washed with sodium bicarbonate solution and with water to neutrality, then it was steam distilled and the product extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane yielded the :,17u acetophenonide of A 19 nor 95,10- pregnene-16a,17a,21-triol-3,20-dione.

In a similar manner A -19-nor-95,10a-pregnene-16a, 17u,21-trio1-3,11,20-trione was converted into its 16a,i7a acetophenonide.

Example V By following the methods of Examples I and II, 19-nor- 9,8,10zz-hydrocortisone, obtained by adrenal incubation of A 19 nor 98,10 pregnene 17ot,21 diol 3,20 dione was converted successively into 16a-hydroxy-19-nor- 7 9,B,10o-hydrocortisone and 16a,l7a-isopropylidenedioxy- A*-19-nor-9,8,1Omregnene-I1fi,21-diol-3,20-dione.

A mixture of 1 g. of the latter compound, 4 cc. of pyridine and 4 cc. of acetic anhydride was kept for 5 hours at room temperature. It was then poured into water and the formed precipitate collected by filtration, washed with water and air dried. Crystallization from acetone-ether gave the 21-acetate of 16a,l7a-isopropylidenedioxy A 19 nor 95,100 pregnene 1113,21- diol-3,20-dione.

Example VI A suspension of 5 g. of 17,20;20,2l-bismethylenedioxy- A -19-nor-9fi,10a-pregnene-3,1l-dione in 37.5 cc. of anhydrous peroxide-free dioxane was treated with 6 cc. of freshly distilled ethyl orthoformate and 4 g. of p-toluenesulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 4 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from race tone-hexane afforded 17,20;20,2l-bismethylenedioxy-3- ethoxy-A -19-nor-9fl, a-pregnadien-1 1-one.

A mixture of 5 g. of the foregoing compound, 2 g. of anhydrous sodium acetate and 100 cc. of acetone was treated with 32 cc. of water and the solution was cooled to a temperature between 0 and 5 C. There was then added 1.1 molar equivalents of N-chlorosuccinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0' and 5 C. for 30 minutes. It was then diluted with water, kept overnight at 0 C. and the precipitate formed was collected, washed with water, and dried under vacuum. The crude 6,8-chloro-A -3-keto intermediate thus obtained was dissolved in 200 cc. of glacial acetic acid and a stream of dry hydrogen chloride was passed through the solution for 4 hours, at approximately C. It was then diluted with water, extracted with methylene chloride and the organic extract washed with water, sodium carbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane afiorded the pure 17,20 ;20,21 bismethylenedioxy 60c chloro A 19-nor- 9fi,10oc-pregnene-3,l l-dione.

A mixture of 2 g. of the foregoing compound and 40 cc. of 60% formic acid was heated on the steam bath for 1 hour, cooled, diluted with water and the precipitate was collected, washed with water, dried, and recrystallized from acetone-hexane, thus affording 6oc-chloro-A -19-nor- 9,8,l0oc-p1'egnene-17u,21-diol-3,11,20-trione.

In a similar manner, the compounds listed below under I gave as final products the compounds listed under 11:

I II

17,20;20,21-bismethylenedioxy-A 19-n0r-9/3, 10a-pregneue-3-one.

lfia-methyl-IZZO: 20, 21-bismethylenedioxy-AHQalor-QB, met-pregnene-3-one.

16a-methyl-17, 20, 21-bismethyl- 6a-chloro-16a-methyl-A -19-norenedioxy-N-lQ-nor-Qfi, loa-preg- 919, 10a-pregnene-17a, 2l-diolnene'3, ll-dione. 3, 11, 20-trione.

6a-chloro-lfia-methyl-A w-nor- 913, lOwpregnenelm, Zl-diol 3, 20-dione.

Example VII 8 A 19 nor 9,8,10a pregnadien 16oz ol 11 one, 17,20;20,21 bismethylenedioxy 6,8 chloro A 19- nor 9,8,10oc pregnen 16a ol 3,11 dione; 17,20;20, 21 bismethylenedioxy 60c chloro A 19 nor 9/3, 100: pregnen 16oz ol 3,11 dione and 60c chloro- ]A 19 nor 9,8,100; pregnene -16oc,17a,21- triol 3,11,

20-trione.

The latter compound was then treated with acetone in the presence of perchloric acid in accordance with the method of Example II, to produce 16a,17a-isopropylidenedioxy 6a chloro A 19- nor 913,100: pregnen 21- 01-3, 1 1,20-trione.

Example VIII 1 g. of 17,20;20,21-bismethylenedioxy-3-ethoxy-A -19- nor-9,B,10a-pregnadiene-ll-one, intermediate of Example VI was dissolved in 25 cc. of dimethylformamide. The solution was cooled to 0 C. and a stream of perchloryl fluoride was passed for 5 minutes; the solution was allowed to come slowly to 20 C.; it was then poured into water -:and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, then with water to neutrality, dried over anhydrous sodium sulfate, and evaporated to dryness. The oily residue was dissolved in 50 cc. of glacial acetic acid and a stream of dry hydrochloric acid passed for a period of 6 hours, while maintaining the temperature around 15 C. The mixture was poured into cold water, the precipitate formed was separated, washed with water, dried and crystallized from acetone-hexane to yield l7,20;20,2l-bismethylenedioxy 60c fiuoro A 19 nor 9B, 1000 pregnene 3,11- dione.

Upon hydrolysis of the bismethylenedioxy group with 60% formic acid, by following the method of Example VI, there was obtained 6aluoro-A -19-nor-9fl,10a-preg nene-17a,2l-diol-3 ,11,20-trione.

In a similar manner, the A -17,20;20,2l-bismethylenedioxy-3-ethoxy intermediates of Examples VI and VII gave as final products: 6wfluoro-A -l9-nor-9fl,lOa-pregnene-17a,21-diol-3,20-dione, 6a fiuoro 16a methyl- A 19 nor 9,3,1000 pregnene 1704,21 diol 3,20 dione, 611 fluoro 16B methyl A 19 nor 95,100- pregnene 170c,21 diol 3,20 dione, 6oz fiuoro 16amethyl A l9 nor 9,8,10oc pregnene 1706,21 diola 3,11,20-trione and 6ot-fiuoro-A -l9-nor-9p,10a-pregnene A solution of 1 g. of 17,20;20,2l-bisrnethylened'ioxy- 6a-fluoro-A -19-nor-9B,l0a-pregnene-3,1l-dione in 50 cc. of tetrahydrofuran was added over a minute period to a stirred suspension of 1 g. of lithium aluminum hydride in cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Saturated solution of sodium sulfate and solid sodium sulfate was added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material, which was purified by crystallization from acetonehexane thus giving 17,20;20,21-bismethylenedioxy-6afluoro-A -10-nor-9fl,1Oa-pregnene-35,1LB-diol.

A mixture of 1 g. of the foregoing compound, 20 cc. of dioxane, and 1.1 molar equivalents of 2,3-dichloro, 5,6-dicyano 1,4-benzoquinone was stirred at room temperature for 3 hours. The hydroquinone formed during the reaction was filtered oil, and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 20 g. of alumina. Crystallization from acetone hexane gave 17,20;20,21-bismethylenedioxy-6rx fiuoro-A -19-nor-9p, 10a-pregnen-1 1 fi-ol-3-one.

The above compound was treated with formic acid, by following the method of Example VI, to produce 60 fiuoro A 19 nor 9,8,1004 pregnene 115,17, 21-triol-3,20-dione.

.9 By the same sequence of reactions, the compounds listed below under I (intermediates of Examples VI, VII and VIII) were converted into compounds under 11:

I II

fia-chloro-lfia-methyl-IY,20;20,21 bismethylenedioxy-AHg-nor- 9,8,10a-pregnene-3,11-dione.

(ta-chloroN-iQ-nor-QB,lots-pregnene-11B,17u,2ltriol-3,20- dione.

Example X Example XI A mixture of 1 g. of l6a,17a-isopropylidenedioxy-M- 19-nor-9B,IOa-pregnen-Zl-ol-3,20-dione, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept overnight at room temperature. It was then poured into water and the formed precipitate collected by filtration, washed with water and air dried. Upon crystallization from acetonehexane there was obtained the pure acetate of oz,l7aisopropylidenedioxy A 19 nor 9,6,10a pregnen 21- 01-3 ,ZO-dione.

In a similar manner, 6a-chloro-A -l9-nor-9,6,l0a-preg nene 1701,21 diol 3,11,20 trione, 6a ChlOl'O-16ocmethyl A 19 nor 93,100: pregnene 17a,2l diol- 3,ll,20-tn'one and 6a-fluoro-A -l9-nor-9p,lilu-pregnene- 11;9,l7a-t1iol-3,20-dione were converted into the corresponding 21-acetates.

Example XII By following the method of the preceding example, the compounds listed below under I were converted into the 21-monoesters II using the appropriate carboxylic acid anhydrides.

triol-3,-dione.

10 Example XIII A mixture of 1 g. of A -19-nor-9fl,lOa-pregnene-16a, l7oz,21-triol-3,20-dione, 4 cc. of pyridine and 4 cc. of acetic anhydride was heated on the steam bath for 1 hour. It was then poured into water, the formed precipitate collected by filtration and air dried. Crystallization from chloroform-ether gave the 16,2l-diacetate of A -19-nor-9B,10u-pregnene-16a,17e,21-triol-3,ZO-dione.

Similarly, 6a methyl A l9 nor-9B,10u-pregnenel6oc,l7cz,2l triol 3,11,20 trione, 6oz fiuoro A 19- nor 95,100: pregnene l6oc,l7oc,21 triol 3,11,20 trione and 6-chloro-A -19-nor-9B,lOa-pregnene-ll B,l6zx,170t, 21-tetrol-3,20-dione were converted into the respective 16,21-diacetates.

When propionic, caproic or enanthic anhydride were used as acylating agents there were obtained the corresponding 16,2l-diesters of such compounds.

Example XIV A mixture of l g. of the acetate of 16a,l7a-isopropylidenedioxy-d -l 9-nor-9fi, lOu-pregnen-Zl -ol-3,20-dione, 2 g. of chloranil and 50 cc. of terbutanol was refluxed for 8 hours. The mixture was cooled, the excess of chloranil filtered off and washed with ethyl acetate and the organic extracts washed with a cold solution of 10% sodium hydroxide until the washings were colorless. It was then dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from methylene chlorideether, after decolorization with alumina give the pure acetate of l6a,17wisopropylidenedioxy-A -19-nor-9B, lOa-pregnadien-Z1-ol-3,20-dione.

Example XV A mixture of l g. of the 2l-acetate of 6a,l6ot-dimethyl- A*19-nor-9,6,lOu-pregnene-l l5,l7a,2l-triol-3,20-dione, 2 g. of chloranil and 10 cc. of xylene was refluxed under an atmosphere of nitrogen for 16 hours. The mixture was cooled, washed with a cold 10% sodium hydroxide solution, then with water, dried over anhydrous sodium sulfate and the xylene was evaporated under reduced pressure. Chromatography of the residue on neutral alumina and recrystallization from acetone-hexane afforded the 2l-acetate of 6,l6a-dimethyl-A l9-nor-9 3,10:x-pregnadiene-l 15,17 a,2 l-triol-3,20-dione.

Example XVI In accordance with the method described in Example XIV, starting from the d -compounds, there were obtained the following 6-dehydro derivatives: 21-acetate of 16oc,17a isopropylidenedioxy-A -19-nor-9,8,1O x-pregna diene-l1p,2l-diol-3,20-dione, ZI-acetate of fi-chloro-A l9-nor-9fi,10e-pregnadiene-l7u,21-diol-3,11,20-trione, 21- acetate of 6-chloro-16a-methyl-A -19-nor-9,8,10a-preg nadiene-17a,21-diol-3,l1,20-trione, 2l-acetate of o-fluoro- A l9 nor-96,1M-pregnadiene-1 lfi,l7cc-2ltfiOl-3,20- dione, 21-propionate of 6-fiuoro-l6u,17u-isopropylidenedioxy A 19-nor-9,8,IOa-pregnadiene-I1B,21-diol-3,20- dione, 16,2l-diacetate of A -l9-nor-9fl,lOe-pregnadienec,17oc2l-tliOl-3,2O-di0n8, Zl-acetate of 6-methyl-A l9-nor-9B,lOe-pregnadiene-l7a,2l-diol-3,11,20-trione, 21- acetate of 6-methyl-A -19-nor-95,lOot-pregnadiene-fia, 2l-diol-3,20-dione, Zl-acetate of 6,16-dirnethyl-A -l9- nor 9,6,10u-pregnadicne-17a,2l-diol-3,-11,20-trione, 21- acetate of A -l9-nor-9,H,IOcx-pregnadiene-I1,8,17w21- triol-3,20-dione, Zl-acetate of A -19-nor-9B,10a-preg nadiene-l7a,2l-diol-3,20-dione and 2l-acetate of A 19-nor-9fl,10a-pregnadiene- 17a,21-dlO1-3,1 1,20-trione.

Example XVII By following the esterification method of Example XI, 500 mg. of the 16,17-acetaldehyde acetal of 6a-methyl- A l9 nor 9,8,10e-pregnene-l6a,l7a,21-triol-3,11,20- trione were converted into its ZI-acetate.

The latter compounds were then dehydrogenated with chloranil in xylene in accordance with the method of 1 1 Example XV, to produce the 16,17-acetaldehyde acetal of 6 methyl A l9-nor-9fi,10a-pregnadiene-16a,17a,21- triol-3,11,20-trione Zl-acetate.

Example XVIII By following the method of Example XIV, "1 g. of 17, 20;20,21 bismethylenedioxy 6ot-chloro-A -19-nor-9/3, 10u-pregnene-3,11-dione was converted into 17,20;20,21- bismethylenedioxy 6-chloro-A -l9-nor-9fi,l0a-pregnadi'ene-3,1'1-dione. Upon hydrolysis of the foregoing compound with 60% formic acid there was produced 6- chloro A 19-nor-9p,10a-pregnadiene-17a,21-diol-3, 20-trione.

Similarly, 1Got-methyl-17,20;20,21-bisn1ethylenedioxy- A -19-nor-918,10a-pregnene-3,1l-dione and 16fl-methyl- 17,20;20,21 bismethylenedioxy A -19nor-95,10a-pregnene-3-one gave as final products 16a-methyl-A -19-nor- 9,8,10va-pregnadiene-17a,21-diol-3,l1,20-trione and 16,8- methyl A 19-nor-9fi,IOa-pregnadiene-17u,2l-diol-3, ZO-dione.

Example XIX A solution of 1 g. of the 21-acetate of A -19-nor-9fi- 10a-pregnadiene-17a,21-diol-3,11,20-trione, in 50 cc. of methanol Was treated with 5 cc. of a 4% aqueous solution of potassium hydroxide; the reaction mixture was stirred for 1 hour under an atmosphere of nitrogen at C.; the mixture was neutralized with acetic acid and the methanol distilled under reduced pressure. The residue was triturated with Water and the solid collected, washed with water, dried and recrystallized from ethyl acetatemethanol, thus producing A-19-nor-9fi,10a-pregnadiene- 17a,21-diol-3,20-dione.

By the same method, all the compounds obtained in Example XVI were saponified, to produce the respective free compounds, namely: 16a,l7a-isopropylidenedioxy- M -l9-nor-9fi,IO-pregnadiene-l1fi,21-diol-3,20-dione, 6- chloro A 19-nor-9,8,lOw regnadiene-l7a,21-diol-3, 11,20 trione, 6-ChlOIO-l6oc-Inetl1yl-A 19-Il0T-9fi,10ozpregnadiene-17u,21-diol-3,11,20-trione, 6-fluoro-A fi-19- nor 9fl,10a-pregnadiene-11fi,17a,21-triol-3,20-dione, 6- fiuoro 16a,17ix-isopropylidenedioxy-A -19-nor-9fi,10apregn-adiene-ll,8,21-diol-3,20-dione, M -19 nor 95,100:- pregnadiene 16cc,17a,21-tI'i0l-3,20-di0ne, 6-methyl-A 19-nor-9,8,1(la-pregnadiene-17u,21-diol-3,11,20-trione, 6- methyl A 19-nor-95,10oz-pregnadiene-l7a,21-diol-3,20- dione, 6,16-dimethyl-A -19-nor-9,B,10a-pregnadiene-17a, 21 diol-3,11,20-trione, A -19-nor-9B,IOa-pregnadiene- 11B,l7oc,21 triol-3,20-dione, A -19-nor-9,8,1Oa-pregnadiene-17u,21-diol-3,20-dione and A -19-nor-9fl,1Ou-pregnadiene-17a,21-diol-3,11,20-trione.

We claim:

1. A compound of the following formula:

I..... 1"? W on H wherein R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms, R represents hydrogen, OR and OR taken together represent the grouping wherein R represents a lower alkyl radical of less than 8 carbon atoms and R is selected from the group consisting a PA 355,, .1 Q t wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms, R represents hydrogen, R represents a hydrocarbon carhoxylic acyl radical of les than 12 carbon atoms, OR and OR taken together represent the grouping wherein R represents a lower alkyl radical of less than 8 carbon atoms and R is selected from the group consisting of hydrogen, lower alkyl, aryl and aralkyl of less than 8 carbon atoms, X is selected from the group consisting of hydrogen and methyl and Y i selected from the group consisting of hydrogen, fl-hydroxy and keto.

6. The 21-acetate of 16a,17a-isopropylidenedioxy-A 19-nor-9,8,10a-pregnene- 11,8,21-diol-3,20-dione.

7. A compound of the following formula:

o rnoR C=O 1..... B 3 o: i

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms; Y is selected from the group onsisting of hydrogen, ,B-hydroxy and keto; R is selected from the group consisting of hydrogen, a-methyl, fi-rnethyl, a-hydroxy, a-acyloxy and R together with the 17mhydroxy group represents the radial wherein R represents a lower alkyl group of less than 8 carbon atoms, R is selected from the group consisting of hydrogen, lower alkyl, aryl and aralkyl of less than 8 carbon atoms, and X is selected from the group consist ing of fluorine and chlorine.

8. 6u-chloro-A -19-nor-9B,l0a-pregnene :,21 diol- 3,11,20-trione.

9. 6a-chloro-16a-methyl-A -19-nor 95,100 pregnene- 11/9,17oc,21-t1i01-3,20-di0fl6.

CHzOR wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms; Y is selected from the group consisting of hydrogen, fi-hydroxy and keto; R is selected from the group consisting of hydrogen, lac-methyl, fl-mcthyl, a-hydroxy, a-acyloxy and R together with the 1704-- hydroxy group represents the radical wherein R represents a lower alkyl group of less than 8 carbon atoms; R is selected from the group consisting of hydrogen, lower alkyl, aryl and aralkyl of les than 8 carbon atoms; and X is selected from the group consisting of hydrogen, methyl, chlorine and fluorine.

15. A -19nor-9B,IOa-pregnadiene-17u-21-dio1 3,20- dione.

16. 16a-methyl-A -19-nor-9fi,10a-pregnadiene 17cc, 21-diol-3,11,20-trione.

17. 6-methyl-A -19-nor-9fl,10a pregnadiene 17,21- diol-3,11,20-trione.

18. 6-fiuoro-A -19nor-9;8,IOaregnadiene 115,170, 2l-triol-3,20-dione.

19. 6-fluoro-16a,17u-isopropylidenedioxy-M- -19 nor- 913,10a-pregnadiene-11/3,21-di0l-3,20-dione.

20. The 21-acetate of 6,16u-dimethyl-A -19-nor-9fl,- IOa-pregnadiene-l1p,l7a,21-tri0l-3,20-dione.

References Cited by the Examiner Brown et al.: J. Org. Chem. (1961), pp. 5033-5036.

LEWIS GOTTS, Primary Examiner. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 